Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity.

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell-cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC. SIGNIFICANCE: A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching.

Associations of gender, race, and ethnicity with disparities in short-term adverse outcomes after pancreatic resection for cancer.

BACKGROUND: Several studies have identified disparities in pancreatic cancer treatment associated with gender, race, and ethnicity. There are limited data examining disparities in short-term adverse outcomes after pancreatic resection for cancer. The aim of this study is to evaluate associations of gender, race, and ethnicity with morbidity and mortality after pancreatic resection for malignancy. METHODS: The American College of Surgeons National Surgical Quality Improvement database was retrospectively reviewed. The χ2 test and Student's t-test were used for univariable analysis and hierarchical logistic regression for multivariable analysis. RESULTS: Morbidity and major morbidity after pancreaticoduodenectomy are associated with male gender, Asian race, and Hispanic ethnicity, whereas 30-day mortality is associated with the male gender. Morbidity and major morbidity after distal pancreatectomy are associated with the male gender. Morbidity after pancreaticoduodenectomy is independently associated with male gender, Asian race, and Hispanic ethnicity; major morbidity is independently associated with male gender and Asian race, and mortality is independently associated with Hispanic ethnicity. CONCLUSIONS: Gender, race, and ethnicity are independently associated with morbidity after pancreaticoduodenectomy for cancer; gender and race are independently associated with major morbidity; and ethnicity is independently associated with mortality. Further studies are warranted to determine the basis of these associations.

Temporal Assessment of Prognostic Factors in Patients With Pancreatic Ductal Adenocarcinoma Undergoing Neoadjuvant Treatment and Resection.

BACKGROUND: The clinicopathologic factors associated with the survival of patients with pancreatic ductal adenocarcinoma (PDAC) during the different phases of neoadjuvant treatment (NT)-at diagnosis, restaging, or postoperatively-remain unclear. METHODS: Data of patients with PDAC who underwent pancreatic resection after NT between 2008 and 2018 were retrospectively collected. Clinicopathologic characteristics and outcomes were compared stratified by resection margin status. Three multivariable regression models (at diagnosis, restaging, and postoperatively) were constructed to assess the temporal impact of different prognostic factors on all-cause survival (ACS) and disease-free survival (DFS). RESULTS: All patients were diagnosed with a nonmetastatic PDAC and were appropriate candidates for NT according to the current National Comprehensive Cancer Network guidelines. From a total of 83 patients, 57 (68.7%) had a negative resection margin >1 mm (R0), whereas 26 patients (31.3%) had a positive resection margin (R1). At diagnosis, planned procedure (P = 0.017) and CA19-9 >100 U/mL (P = 0.047) were independent prognostic factors of decreased ACS. At restaging, planned procedure (P = 0.017), FOLFIRINOX (P = 0.026), and tumor size >30 mm (P = 0.030) were independent prognostic factors for increased and decreased ACS, respectively. Postoperatively, R0 was an independent prognostic factor for improved ACS (P = 0.005) and DFS (P = 0.002), whereas adjuvant therapy (P = 0.006) was associated with increased ACS. Lymph node involvement (P = 0.019) was associated with decreased DFS. CONCLUSIONS: At diagnosis, restaging, and postoperatively, different, relevant clinicopathologic factors significantly impact the survival of patients with nonmetastatic PDAC undergoing NT. An R0 resection remains the most important prognostic factor and therefore should be the primary goal of surgical treatment in the neoadjuvant setting.

Identifying Hospital Cost Savings Opportunities by Optimizing Surgical Approach for Distal Pancreatectomy.

BACKGROUND: The economic implications of relevant clinicopathologic factors on the surgical approach to distal pancreatectomy (DP) should be clearly defined and understood to potentially allow the implementation of cost reduction strategies. METHODS: Administrative and clinical datasets of patients undergoing a DP between 2012 and 2016 were merged and queried. Univariate and multivariate analyses were used to identify clinicopathologic predictors of cost differentials for minimally invasive DP (MIDP) relative to open DP (ODP). Time trends in cost were also assessed to identify opportunities for cost containment. RESULTS: Among two hundred and twenty five patients, 128 underwent an ODP (57%) and 97 a MIDP (43%). The DP groups were comparable with regard to relevant perioperative and disease characteristics. Total hospitalization and total OR costs for MIDP were significantly lower (- 12%, P = 0.0048) and higher (+ 16%, P < 0.0001) respectively, compared to ODP. On univariate analysis, age > 60 (- 12%, P = 0.0262), BMI > 25 (- 10%, P = 0.0222), ASA class ≥ 3 (- 11%, P = 0.0045), OpTime > 230 min (- 16%, P = 0.0004), and T stage ≥ 3 (- 8%, P = 0.0452) were associated with decreased total costs after MIDP compared to ODP. Linear regression analysis revealed that BMI > 25 (Estimate - 0.31, SE 0.15, P = 0.0482), ASA class ≥ 3 (Estimate - 0.36, SE 0.17, P = 0.0344), and T stage ≥ 3 (Estimate - 0.57, SE 0.26, P = 0.0320) were associated with decreased hospitalization costs after MIDP compared to ODP. Overtime, total hospitalization cost for MIDP increased from - 21 to 1% (P = 0.0197), while OR costs for MIDP decreased from + 41% to - 2% (P = 0.0049), nearly equalizing the cost differences between ODP and MIDP. CONCLUSIONS: Relevant clinicopathologic factors predicted decreased hospitalization costs after MIDP relative to ODP. In equivalent stages of disease, optimizing the surgical approach to DP based on specific clinicopathologic characteristics may afford significant cost-saving opportunities.